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Injectable photoreactive gel and biological adhesive help new cartilage grow

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Introduction

This is a production of the National Institute of Biomedical Imaging and Bioengineering, part of the National Institutes of Health

Host-Margot Kern: Every year, hundreds of thousands of Americans undergo surgery to repair torn hyaline cartilage—that is the tough, flexible tissue that acts as a shock absorber between bones. Yet, outcomes for cartilage repair are typically poor. The reason is that unlike other tissues in the body, cartilage lacks its own blood supply, which normally bathes damaged tissue and provide factors that promote regeneration.

Host-Margot Kern: Currently, the first-line therapy for cartilage repair is a technique called microfracture surgery in which tiny holes are drilled into the bone located directly below missing cartilage in order to release bone marrow into the damaged space. Because bone marrow contains a mixture of stem cells and blood, the resulting clot provides an enriched environment that promotes cartilage regeneration.

Host-Margot Kern: Yet, only half of these surgeries are considered successful in the long-term. One issue is that the regenerated cartilage is a mixture of smooth hyaline cartilage and fibrous scar-like tissue. This fibrocartilage doesn’t function as well as pure hyaline cartilage as a cushion between joints. Another issue is that the regenerated cartilage rarely integrates fully with the patient’s existing cartilage and this prevents it from becoming functional.

Host-Margot Kern: Dr. Rosemarie Hunziker is a program director in charge of overseeing NIBIB’s grant portfolio for tissue engineering. Over the years, she’s witnessed many attempts by doctors and researchers to devise novel techniques for cartilage repair.

Hunziker: I’ve seen just about everything from harvesting healthy cartilage from another part of the body and then directly transplanting it, although way through to complex formulations of scaffolds and cells grown in the lab and then implanted as a unit. The problem has always been, how to get the newly-generated tissue to integrate into a patients’ existing tissue so that it becomes functional.

Host-Margot Kern: But Dr. Jennifer Elisseeff, a tissue engineer at Johns Hopkins University, may have provided a promising new alternative. Elisseeff builds hyaline cartilage in her lab, a process that involves planting chondrocytes—which are cartilage-producing cells—into a biological scaffold and then incubating them in conditions similar to those found in the human body. Elisseeff says choosing the right scaffold material is critical for producing high-quality cartilage.

Elisseeff: As we’ve been learning more about biomaterials and how cells respond to them, we’ve also learned that chondrocytes, the cells that make up cartilage, prefer to be in a softer material as the tissue’s developing.

Host-Margot Kern: Elisseeff’s lab creates hydrogel scaffolds, which are smooth, flexible, and have a high water content. Not only do these hydrogels encourage the production of hyaline cartilage, but they also deter the development of unwanted tissue.

Elisseeff: We want to reduce scar formation and bone formation and these types of hydrogel scaffolds are able to do that.

Host-Margot Kern: After several years of growing high-quality cartilage in the lab, Elisseeff predicted that if she could introduce her hydrogel scaffold into a patient following microfracture surgery, she might be able to influence the quality of the cartilage regenerated.

Host-Margot Kern: But implanting a scaffold into an irregularly shaped space where cartilage has broken off is no easy task. Even more difficult is getting the scaffold to adhere to the slippery walls of a patient’s surrounding cartilage, a step that’s crucial for the new cartilage to become functional.

Host-Margot Kern: With the support of NIBIB funding, Elisseeff began to develop two novel technologies to overcome these hurdles. The first was a photo-active hydrogel that could be injected as a liquid into an irregularly shaped cartilage defect and then solidified upon exposure to a light source. The second technology was a biological adhesive that could bond to both the hydrogel and to specific proteins found on the surface of cartilage tissue, essentially cementing the scaffold in place.

Elisseeff: We wanted to be able to bond the hydrogel in tough environments, and then it also serves a biological role to help stimulate tissue development at that fragile interface.

Host-Margot Kern: Elisseeff’s photo-active gel and biological adhesive were recently tested in a clinical trial involving 18 patients. Fifteen patients received microfracture with the gel/adhesive combo and three received microfracture alone.

Host-Margot Kern: The growth of new cartilage was evaluated post-surgery using an innovative MRI technique, also developed by an NIBIB grantee, Dr. Gary Gold of Stanford Univeristy. The technique can distinguish between fibrous and smooth cartilage and gives doctors a way to monitor cartilage growth at sequential time-points without conducting a tissue biopsy, a procedure that’s detrimental even when taking just a tiny amount of cartilage.

Host-Margot Kern: In the trial 84% of the defect was filled with new cartilage in patients who received the gel/adhesive combo compared to just 64% in patients who received microfracture alone. And this new cartilage closely resembled the patient’s native cartilage at six months as verified by MRI. Additionally, patients who received the gel/adhesive combo reported a decrease in pain at six months post-surgery.

Host-Margot Kern: Hunziker says the study is exciting because it combines advancements in the fields of bioimaging and bioengineering to solve a long-standing problem in the field of cartilage repair.

Hunziker: Dr. Elisseeff’s lab may have found that elusive holy grail which is tissue integration. But it’s also important to note the significance of the novel MRI techniques that were used here to evaluate the new cartilage non-invasively. It was really a critical component to the study, because if we didn’t have it, we wouldn’t have an objective method for determining whether Elisseeff’s complex strategy was really working.

Narrator: This is a production by the National Institute of Biomedical Imaging and Bioengineering, part of the National Institutes of Health.

Boone: A long time ago, I was thinking about how we could better det ect breast cancer. If you really wanted to improve contrast resolution for detecting breast cancer, CT would be the way to go.

Narrator: You’re listening to NIBIB grantee Dr. John Boone, Vice Chair of Radiology and Professor of Radiology and Biomedical Imaging at the University of California, Davis. Boone has spent the past decade developing a dedicated breast CT scanner that allows radiologists to view the breast in three dimensions.

Boone: Rather than acquiring just two images which is what a mammogram is, we actually have an apparatus that rotates around the breast 360 degrees and it acquires 500 images around the breast, and that provides the data set necessary to put that information into a computer and it comes out with a three dimensional set of images of the breast.

Narrator: The new technology could help radiologists detect hard-to-find tumors, especially in women who have dense breasts, which is commonly seen in younger woman. Dense breasts have higher percentages of connective and glandular tissue and when looking at a two dimensional x-ray of the breast, it can be difficult to view small tumors which may be located behind many layers of dense tissue. A CT scan which takes x-rays from many different angles could potentially reveal these tumors.

Boone: With breast CT, because we generate a 3D volume data set, the radiologist can scan through the images and that allows you to eliminate some of that overlying tissue and have a higher probability of detecting cancer we think.

Narrator: So why aren’t women currently offered a CT scan for routine cancer screening? The issue is that a conventional CT scan of the chest requires a hefty dose of radiation.

Boone: If you look at a whole body CT scanner, it scans the patients with the patient lying on the table and the x-ray tube and detectors go around the entire patient’s chest which means and that means you have to turn up the dose levels to penetrate the woman’s entire thorax.

Narrator: When Boone first announced his intention to build a CT scanner for detecting breast cancer, his colleagues were skeptical. They said there was no way he could screen for breast cancer using CT at a radiation dose comparable to mammography. But Boone was determined, and he began to design a novel CT scanner that didn’t require x-rays to pass through the chest.

Boone: The first step towards reducing radiation dose is to design a scanner that scans only the breast.

Narrator: In Boone’s scanner, a woman lies prone on a large table with her breast hanging through a hole in the middle. The scanner rotates just around the breast taking hundreds of x-rays without passing any through the chest.

Narrator: In 2001, using a computer simulation, Boone demonstrated that his proposed breast CT scanner would deliver a radiation dose comparable to standard mammography. In 2004, his lab became the first to image humans using dedicated breast CT. Since then, Boone has scanned over 600 women in a series of clinical trials and results from these showed that breast CT is significantly better at revealing tumors than traditional mammography.

Narrator: As an added bonus? Boone’s scanner doesn’t require compression of the breast.

Boone: Most women who have had mammograms recognize that the breasts are fairly aggressively compressed. In some women it’s very painful and in others it’s just sort of painful. We eliminate compression with breast CT.

Narrator: With support from NIBIB over the year, Boone has continued to develop his dedicated breast CT platform by incorporating additional imaging capabilities such as positron emission tomography also known as a PET scan

Narrator: In PET imaging, a patient is given an injection of a radioactive sugar molecule which quickly accumulates at tumor sites due to their increased rates of metabolic activity.

Boone: On our device, we actually do the CT scan and that gives a high- resolution anatomical picture of the breast. And then we do the PET scan and that picks up the emissions that are given off by the tumor that’s accumulated this agent. Usually we color that and lay it onto the grey scale breast image and it provides a pretty dramatic image of the tumor if there’s c a tumor there.

Narrator: Boone is also collaborating with the University of Chicago to develop computer aided-detection software in order to help radiologists view the hundreds of images generated by a CT scan.

Boone: We’re essentially asking radiologists to move from looking about two images per breast to looking at about 500 images per breast and radiologists are busy people and that would in general preclude any realistic deployment of such a device.

Narrator: Their goal is to produce software that uses algorithms to automatically detect tumors and then classify them as benign or malignant, a process that could both save time and improve the accuracy of diagnoses.

Narrator: Though dedicated breast CT is currently only approved for research purposes, Boone believes it won’t be too long before breast CT makes it into the clinic.

Boone: There are several companies around the world that are developing breast CT scanners. They have to go through the approval process which is quite lengthy but it would be realistic to think that breast CT technology will be available in perhaps 5-8 years in the United States.

Narrator: Until then, Boone and his lab will continue to improve the breast CT platform. They are currently focused on ways that CT could be used to provide real time image guidance for biopsy needle placement and minimally invasive tumor ablation.

Narrator-Kern: This is a production by the National Institute of Biomedical Imaging and Bioengineering—part of the National Institutes of Health

Shea: The body has natural mechanisms for kind of shutting down an immune response that’s inappropriate and we’re really just looking to tap into those natural mechanisms.

Narrator-Kern: That’s Dr. Lonnie Shea, professor of bioengineering at Northwestern University referring to a recent advance in the pursuit of a safer, more efficient way to treat autoimmune diseases. Shea, in collaboration with Dr. Stephen Miller, also of Northwestern, have come up with a way to selectively inhibit the part of the immune system responsible for causing these diseases. Their most recent work, published in Nature Biotechnology, describes an innovative method for treating multiple sclerosis in mice. Dr. Miller explains just how the immune system is involved in the development of MS:

Miller: The immune response starts to attack the myelin membrane in the central nervous system. As a part of the disease, activated T cells enter the CNS and cause the destruction of myelin that leads to impairment of electrical function from the central nervous system to the muscles resulting in paralysis.

Narrator-Kern: Miller went on to explain that self-reactive T cells are responsible for generating a host of autoimmune diseases including rheumatoid arthritis and type 1 diabetes. Currently, autoimmune diseases are treated with a class of drugs called immunosuppressants, but Miller says these drugs have major drawbacks.

Miller: You’re not only trying to treat the autoimmune disease, you also make the individual susceptible to what we call opportunistic infections, or infections that those of us with healthy immune systems can normally deal with quite readily.

Miller: People on long-term immunosuppressant drugs are also susceptible to higher rates of cancer development because their immune system is not properly used to patrol the body looking for mutant cells that might become cancers.

Narrator-Kern: Miller says the holy grail of treating autoimmune disease is by a phenomenon called tolerance.

Miller: And what tolerance simply means is, in order to treat the disease, what you’re trying to do is specifically inactivate only the T cells that are responsible for damaging the self-tissue

Narrator-Kern: Miller’s lab has spent the past several decades developing a novel method for inducing tolerance. In the late 70’s, the lab discovered that if they attached antigens (or tiny portions of a protein) to dying white blood cells and then injected these antigen-coupled cells into a mouse, the mouse’s immune systems would become tolerant to the antigen.

Narrator-Kern: The method works because the body is constantly helping the immune system distinguish between antigens that belong to the body and those that are foreign and should be attacked. One way it does this is by presenting bits of protein found within dying cells to T-cells located in the spleen. Any T-cells capable of binding to these proteins become suppressed. Using this method, Miller’s lab was able to treat various animal models of autoimmune disease over the years, simply by changing the antigen coupled to the dying cells.

Narrator-Kern: But Miller anticipated problems translating his results in the lab to a potential treatment for humans. The issue was the need to use dying cells as antigen carriers:

Miller: Using the cellular therapy is extremely expensive and complex and requires that this therapy would be carried out at a large medical center.

Narrator-Kern: It was at this point that professor Lonnie Shea was pulled into the mix.

Shea: You know in our conversations, it became obvious that while his approach was incredibly successful and he’d done tremendous science in terms of understanding how that process worked that the translation would really be facilitated by using something other than the cell as the carrier for the peptide.

Narrator-Kern: That something ended up being microscopic biodegradable particles to which the lab attached specific antigens, in their case, a peptide of myelin.

Shea: A human hair is approximately a hundred microns in diameter, and so these particles are roughly 500 times smaller than a human hair.

Narrator-Kern: To their amazement, the antigen-bound particles worked just as well if not better than the apoptotic cell carriers. And, when they injected their particles intravenously into mice conditioned to develop an experimental form of MS, the vast majority of mice never developed it. They were also able to halt the progression of the disease by injecting the mice just after the first symptoms of MS emerged.

Narrator-Kern: Shea says one advantage of their particles is that they’re made from a substance that already has FDA approval

Shea: This particle has been used as biodegradable sutures for many years. The same material has been used in drug delivery microspheres for years. We’ve made them a different size, but ultimately the material is something that’s readily accepted by the body.

Narrator-Kern: Miller believes that the particles could be adapted to potentially treat a wide range of diseases and conditions involving the immune system:

Miller: We’ve also shown that these antigen-coupled nanoparticles can be used in animal models of allergic disease. We found in unpublished results that we can attach allergens onto these particles and inhibit the development of an allergic immune response. A third potential use for this, we’re envisioning being used to induce tolerance to to promote the acceptance of cell and tissue grafts between individuals.

Narrator-Kern: Shea points to the unique collaboration that lead to the successful development of these particles.

Shea: This is just a tremendous example of the opportunities of interdisciplinary work. My lab has the materials but we don’t have the biological expertise that Dr. Miller has. At the same time, he has tremendous biological expertise but necessarily didn’t have the tools by which to modify or create a particle of our own that would have all the properties we would want.

Narrator-Kern: Miller’s hopeful that years of manipulating the immune system in a lab environment might soon yield a treatment for patients.

Miller: I’ve been working in the field of immune tolerance my whole scientific career. It took 30 years to get from animal experiments to our initial phase 1 clinical trials using the antigen-coupled apoptotic cells. We’re hoping it only takes a year or two to get into the phase 1 clinical trial using the particles.

Featured Photos

Upon entering cells, nanoparticles begin to biodegrade, shedding their polyethylene glycol coat (green) and releasing their drug payload. Here the cell skeleton is shown in red, the cell nucleus in blue. The green color inside the cell demonstrates that the nanoparticles entered the cell.

Image of a new vaccine patch that can be self-administered and does not produce biohazardous waste. The microneedles in the patch inject the vaccine into the epidermis layer and then dissolve.
Source: Mark Prausnitz, Georgia Tech